Delayed or impaired wound healing can result from various conditions. These include diabetes (Rosenberg (1990) Nurs. Clin. North Am. 25:247-261), peripheral vascular disease (Kamler et al. (1992) Adv. Exp. Med. Biol. 316:419-424), advanced age (Reed (1998) Geriatrics 53:88-94), malnutrition (Young (1988) Heart Lung 17:60-67), immune suppression and corticosteroid use (Uthoff et al. (1995) Ann. Thorac. Surg. 59:277-282), psychological stress (Kiecolt-Glaser et al. (1995) Lancet 346:1194-1196), and cancer radiotherapy and chemotherapy (Mason et al. (1992) Clin. Oncol. 4:32-35). There is presently no standard therapy for delayed or impaired wound healing other than supportive care.
The initiation and control of concerted processes responsible for wound healing are governed by polypeptide molecules known as growth factors (Bennett et al. (1993) Review, Am. J. Surg. 165:728-737). These polypeptides can be categorized by sequence homology or by function.
Based on sequence homology, growth factor family groups include epidermal growth factor family (EGF) (Brown et al. (1988) Ann. Surg. 208:788-794), platelet derived growth factor family (PDGF) (Hill et al. (1991) Comp. Biochem. Physiol A. 100:365-370), insulin-like growth factor family (IGF) (Suh et al. (1992) Endocrinology 131:2399-2403), transforming growth factor-beta family (TGF-3) (Cox (1995) Cell Biol. Int. 19:357-371), fibroblast growth factor family (FGF) (Kusstatscher et al. (1995) J. Pharmacol. Exp. Ther. 275:456-461), vascular endothelial growth factor family (VEGF) (Frank et al. (1995) J. Biol. Chem. 270:12607-12613).
Growth factors can be grouped functionally, according to the role they play in initiating and controlling the various phases of wound healing. A first group consists of chemotactic growth factors, i.e., those that attract inflammatory cells such as monocyte/macrophage and fibroblasts to the cell site. A second group consists of growth factors that act as mitogens to stimulate cellular proliferation. A third group consists of that growth factors that stimulate angiogenesis. A fourth group consists of growth factors that affect the production and degradation of the extracellular matrix. A fifth group of growth factors consists of those that influence the synthesis of cytokines and growth factors of neighboring cells.
Growth factors constitute a subclass of cytokines. Growth factors are distinguished from other cytokine subclasses by their ability to act as mitogens, chemoattractants and proliferation inducers on cells of epithelial, endothelial, and mesenchymal origins. In particular, the pleiotropic growth factor TGF-.beta. is important in orchestrating the wound healing response (Beck et al. (1993) J. Clin. Invest. 92:2841-2849).
Exogenously applied growth factors (particularly BFGF, PDGF, EGF, and TGF-B) have been used to stimulate wound healing (Puolakkainen et al. (1995) J. Surg. Res. 58:321-329; Greenhalgh et al. (1996) J. Trauma 41:159-167). A difficulty in using this approach has been in formulating the growth factors in such a way as to ensure their sustained slow release in a biologically active form (Davies et al. (1997) J. Biomater. Appl. 12:31-56; Nicoll et al. (1997) Biomaterials 18:853-859; Arm et al. (1996) Biomaterials 17:703-709; and Fukunaga et al. (1994) J. Pharm. Pharmacol. 46:168-171).